Study design and setting
This is a parallel, non-inferiority, randomized controlled clinical trial aiming to compare the effect of Ma's bamboo-based medicinal moxibustion therapy and regular acupuncture therapy on low back pain in LDH patients.The patients will be enrolled among outpatients and inpatients from the acupuncture departments of No.1 Affiliated Hospital of Guizhou University of Traditional Chinese Medicine,No.2 Affiliated Hospital of Guizhou University of Traditional Chinese medicine.Eligible patients will be randomly assigned to a Ma's bamboo-based medicinal moxibustion therapy group and an acupuncture group in a 1:1 ratio.All items from the World Health Organization Trial Registration Data Set are shown in Table 1. The study flowchart is provided in Figure 1. A Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist and figure are provided respectively in Additional file 1 and Figure 2.
The protocol has been approved by the ethical committee of No. 1 Affiliated Hospital of Guizhou University of traditional Chinese Medicine (ethical approval number: k2020–039), and the study is registered at Chinese Clinical Trial Registry,ChiCTR(Registration number: ChiCTR2000038725; registration date: Septembe 29, 2020).
The diagnostic criteria are:
- Lower limb radiative pain, of which the pain location was consistent with the corresponding affected innervation area
- Lower limb sensory abnormalities, with decreased superficial sensation of the skin in corresponding affected innervated area
- Positive result of Lasegue test, Bragard test, Lasegue test of the unaffected side, or femoral nerve stretching test
- Weaker tendon reflex than that of the unaffected side
- Muscle weakness
- Intervertebral disc herniation indicated by lumbar MRI or CT, of which the nerve compression was consistent with the symptoms, signs of the affected nerves
- In the first five criteria, patients could be diagnosed as LDH when meeting three of them combined with Item 6
- Intervertebral disc bulging, with outward bulge of the annulus fibrosus of the whole intervertebral disc uniformly
- Localized herniation of the intervertebral disc, rupture of inner layer of annulus fibrosus of intervertebral disc, and partial herniation of nucleus pulposus
- Intervertebral disc herniation, rupture of most annulus fibrosus of the intervertebral disc, with intact outer annulus fibrosus merely, and the nucleus pulposus confined to the intervertebral disc
- Prolapse of the intervertebral disc, rupture of all annulus fibrosus of the intervertebral disc, nucleus pulposus tissue protruding out of the intervertebral disc and bound by the posterior longitudinal ligament
- Sequestered disc herniation, nucleus pulposus tissue protruding out of the annulus fibrosus and posterior longitudinal ligament, and sequestered in the spinal canal
Note: In this trial, patients with pathological classification of intervertebral disc bulging, localized herniation of the intervertebral disc and intervertebral disc herniation will be selected for experiment according to the long-term treatment experience and practice by using Ma's bamboo-based medicinal moxibustion therapy.
1. Low back pain due to cold-dampness evil
The presence of a history of suffering from cold in the waist, aggravation of symptoms when the weather changes or when there is cloudy, rainy or cold weather, with severe cold and pain in the waist, accompanied by numbness or contracture that restricts the body movements of bending or raising up, even with pain involving the lower limbs
2. Low back pain due to dampness-heat evil
Severe and heat pain in the waist, aggravation of symptoms in summer-heat and damp, cloudy and rainy weather, and possible alleviation after activities, accompanied by heavy body and feeling of sleepy, short voiding of reddish urine, yellow and greasy fur on the tongue, as well as soft and frequent pulse or wire and frequent pulse
3. Low back pain due to static blood
The presence of a history of strain or old injury in the waist, aggravation of symptoms when getting up in the morning, tired and sitting for a long while., with stiffness of the muscles on both sides of the waist, pain like the stabbing of a needle, and pain in a fixed site
4. Low back pain due to kidney deficiency
Major manifestations of soreness and weakness, with dull pain, alleviation when pressing and lifting, accompanied by weakness in legs and knees with relief when lying down and repeated onset, with fatigue and hypersomnia, and thready pulse as well
Note: In our study, patients with all the types based on syndrome classification mentioned above will be included for experiment according to the long-term treatment experience and practice by using Ma's bamboo-based medicinal moxibustion therapy.
Patients who meet all of the following criteria were enrolled in the trial:
- Patients who meet the above diagnostic criteria and pathological classification, with the lesion located in L3-S1
- Patients aged 18-65 years, males or females
- Patients with the course of disease≥6 months
- Drug users with drug withdrawal for 4 weeks, and non-drug users with discontinued treatment for 2 weeks
- Patients with 3≤VAS scores≤6
- Willingness to sign written informed consent
Patients who meet any of the following criteria were excluded from the trial:
- Patients with acute onset of low back pain in lumbar disc herniation
- Patients with low back pain caused by other causes
- Patients with other diseases requiring combined treatment using anti-inflammatory and analgesic drugs
- Patients during pregnancy, lactation or pregnancy preparation
- Patients with rash, skin damage, ulcers or other infectious diseases at the waist
- Patients with serious diseases of the heart, liver, kidney, blood system, etc.
- Patients with mental disorders or communication disorders who could not cooperate
- Patients with high fever and Yin deficiency
The trial is design to determine the efficacy of Ma's bamboo-based medicinal moxibustion therapy on low back pain in LDH and prove that its clinical efficacy is not inferior to normal acupuncture therapy. Therefore, we chose a non-inferiority trial design. According to the previous literature[8, 13] and the joint consideration of clinicians and statisticians, it is assume that the standard deviation of VAS score reduction of patients using bamboo-based medicinal moxibustion is 2.0, the non-inferiority limit valueis equal to 0.78, with a power (1-β) of 0.9 (α= 0.025, one-sided), and the number of subjects is equal in the two groups. By using PASS(Power Analysis and Sample Size)15 software, the sample size (N) of the experimental group and the control group are 140 cases respectively. According to the 10% drop-out rate, each group needs at least 156 patients, 312 patients will be recruited in the trial.
Randomization and blinding
There are two investigators at each center (referred to as A and B). Investigator A is responsible for entering baseline data of patients and perform randomization, but he will not know the grouping details and will not participate in the treatment. Investigator B is responsible for performing treatment according to the grouping. At each visit, A is responsible for collecting data and entering the data in the electronic data capture (EDC) system. The therapist and the data collector are separate. Statisticians are responsible for data processing and are not aware of the grouping until the end of the trial. Stratified block randomization will be carried out by third party statisticians who will be not involved in any other part of the trial. Central randomization will be conducted by INTELLIGENCE FUTURE Soft Co., Ltd.(Tianjin, China). A random sequence will be generated with SAS 9.2 (SAS Institute, Inc.,Cary, NC, USA) by an independent statistician who is not involved in the study, and the sequence will be stored in acentral randomization system (interactive web response (IWR) system). The patients will be stratified based on the two different centers and randomly assigned to the Ma's bamboo-based medicinal moxibustion group and the acupuncture group in a 1:1 ratio.The Ma's bamboo-based medicinal moxibustion group will receive Ma's bamboo-based medicinal moxibustion therapy.Regular acupuncture therapy will be performed on the acupuncture group.
In this trial, patients and therapists will not be blinded due to the uniqueness of the two therapies. Investigators and statisticians will be blinded. Treatment, data collection and data analysis will be conducted by trained practitioners, data collectors and statisticians, respectively, all blinded to one another in order to ensure the reliability of the results.
The conditions for unblinding are: 1) infection or other adverse events, and these patients will be withdrawn from the trial; or 2) the end of the trial and data analysis.
All treatments will conduct in the outpatient treatment rooms of the two centers.The therapists will be not involve in the other parts of the trial. The treatments will be performed every day, for a total of 12 treatments.All the treatments will be completed with in 13 days. The assessments of the treatments will be performed after treatment, on the 7th day, the 14nd day, and the 28th day.All practitioners involved in the trial are trained and registered professionals. Acupuncture was performed by primary physicians with >5 years of experience at each center. A training program to standardize all manipulations and filling of a case report form (CRF) will be provided before the trial. Investigators will inform all patients about the possible inconveniences from the trial.
Ma's bamboo-based medicinal moxibustion group
Prior to the treatment, the components of this traditional Chinese medicine prescription will be ground into fine powder, following by mixing and sealing for further use, which include Wei Ling Xian (Clematidis Radix Et Rhizoma),Du Huo( Angelicae Pubescentis Radix),Rou Gui( Cinnamomi Cortex),Xi Xin(Asari Radix Et Rhizoma),Chuan Xiong( Chuanxiong Rhizoma), Sang Ji Sheng(Taxilli Herba), Gui Zhi(Cinnamomi Ramulus), etc. (250g each). Components such as Wei Ling Xian(Clematidis Radix Et Rhizoma),,Ji Xue Ten (Spatholobi Caulis),Chuan Niu Xi( Cyathulae Radix), Xi Xin(Asari Radix Et Rhizoma), Du Huo( Angelicae Pubescentis Radix),Chuan Xiong( Chuanxiong Rhizoma), Sang Ji Sheng(Taxilli Herba) and Rou Gui( Cinnamomi Cortex) (200g each) will be placed in 21000mL Liquor and Spirits of 50° for 7 days for subsequent use. Bamboo tube with an inner diameter of 4.5-5.5cm is taken with the stem nodes removed, and cut with a hacksaw according to the specification of 4.5-5.5*4cm (inner diameter * height). Then, with the removal of the bamboo bark on the surface, the edge of the bamboo tube is polished smooth and round to prepare a unique medicinal moxibustion tool. After that, 15g of medicinal powder and 20ml of medicinal wine are mixed evenly, and the finished product is then placed into the medicinal moxibustion tool to press into medicinal cake. In the next step, 3g moxa (Suzhou Medical Appliance Factory, Suzhou, Jiangsu, China) are made into several moxa-cone with moderate hardness (2.5 cm in height and 2 cm in diameter), which are then place on the compressed powder and ignite for preheating. The moxa-cone are replaced when the medicinal cake will be warm. The patients are informed to take the prone position with the moxibustion sites exposed.L1-L5Jia ji(EX-B2), Shenshu (BL23), Mingmen Point(GV4) and Yaoyangguan(GV3)are selected for moxibustion. The acupoint positioning is perform in accordance with Nomenclature and location of acupuncture points(GB/T 12346-2006). The therapist should ensure that the moxibustion site of the patient is continuously warm without burning pain. The moxa-cone are replaced after burning out, with a total of 3 cones, and the treatment is last for about 40min.
The acupuncture group will be treated with 0.30×40 mm,and 0.30×50 mm disposable sterilized filiform needles (Suzhou Medical Appliance Co., Ltd., Suzhou, Jiangsu,China) applied to the Shenshu (BL23), Dachangshu (BL25) ,Weizhong(BL40), L1-L5Jiaji(EX-B2), and Ashi points.The acupoint selection is formulated according to the major acupuncture point prescription in the Evidence-Based Guidelines of Clinical Practice with Acupuncture and Moxibustion Low Back Pain. Practitioners will performe the treatment according to the national standard of acupuncture manipulation[16, 17]. The needles will be inserted and manually manipulated until de qi is achieved.
Combined use of drugs
During the whole period of observation, it is suggested that the patients do not use drugs or other methods for the treatment of low back pain in LDH in addition to the experimental scheme. During the treatment period, if the patients take medication by themselves or use other methods of treatment due to aggravated symptoms and unbearable lumbar pain, they will be withdrawn from the trial. The clinicians will make the appropriate treatments according to the specific conditions of the patient until the symptoms are improved.
Primary outcome measures
We will use the visual analogue scale as the primary outcome measure .VAS is one of the sensitive and reliable methods for pain measurement. VAS scores ranged from 0 point to 10 points, which were described in details as follows: 0: painless; Less than 3 points: slight pain that can be tolerable; 4-6 points: pain to affect the sleep, which can be tolerated; 7-10 points: gradually intense pain, which is unbearable and affects appetite and sleep.
Secondary outcome measures
Serum β-endorphin and serum substance P will be used to assess improvement of pain in LDH. Previous clinical studies [19, 20]have reported that the reduction of pain in LDH might be correlated with the levels of serum β-EP and SP, which may be considered as one of the analgesic mechanisms of reducing low back pain in LDH. Methods of detection: At baseline and after the end of treatment, 4ml venous blood samples were collected from patients on an empty stomach in both groups, which were placed in serum separation tubes. Blood samples were then centrifuged at 1000×g for 20 min, the supernatant was then collected and stored in refrigerator at -20℃ or -80℃ for further measurement.Enzyme-linked immunosorbent assay(ELISA)was used for determination, and the operation was carried out in strict accordance with the instructions of the kit. The test is conducted by the Central Laboratory of No.1 Affiliated Hospital of Guizhou University of Traditional Chinese Medicine.
Oswestry disablity indes(ODI) [21, 22]is one of the most widely used scoring scales for functional outcome evaluation of patients with low back pain. It consists of 10 questions, including pain intensity, self-care, lifting, walking, sitting, standing, interference with sleep, sexual life, social life and tourism. A higher score may indicate a more serious dysfunction.
Modified Japanese Orthopaedic Associatio low back pain (M-JOA) score is a frequently used scale. It includes subjective symptoms (lumbar pain, lower limb radiative pain and numbness), objective symptoms (paravertebral tenderness, muscle tension, Lasegue test and femoral nerve stretching test) and daily behavior ability (working ability, sleep, bending and lifting). The score ranges from 0 point to 30 points, and a lower score may reveal a milder condition.
Before the start of the trial, the investigators will fully in-form the patients of the benefits and the possible inconvenience of the study. The patients will sign the informed consent form and volunteer to participate in the study. MRI of the lumbar vertebrae，laboratory examination, and twelve times of treatment will be free of charge in order to improve the adherence of the patients. The baseline data of each patient (name,gender, age, address, telephone or contacts of immediate family members) will be recorded in detail, hereby to facilitate the supervision of patients’ adherence. The cases of drop-out, withdrawal, and discontinuation will be recorded and followed up by telephone or even followed up at patients’ homes if necessary.
Data monitoring and management
Our study group will set up a special data monitoring committee for data management and quality control, which consists of hospitals, company, and institute.
Quality control system
All three-level quality monitoring system was established. Clinical research associates (CRAs) were assigned for data monitoring. Level 1 monitoring requires the CRAs in the two hospitals (No. 1 Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No. 2 Affiliated Hospital of Guizhou University of Traditional Chinese medicine) to monitor the quality of the CRFs once a week, fill out the monitoring report, and report to the principal investigator (PI) in time. Level 2 monitoring requires the CRA from INTELLIGENCE FUTURE Soft Co., Ltd to conduct quality monitoring once every six months, fill out the monitoring report, and report to the project leader of INTELLIGENCE FUTURE in time. Level 3 monitoring requires the person in charge or the technical backbone at the institute of Chinese Medical History and Literature, China Academy of Chinese Medical Sciences to monitor once or twice annually.
Data management platform
The data management platform was set up by INTELLIGENCE FUTURE soft Co., Ltd. It includes the IWR and EDC systems. It includes nine modules, including data entry and statistics. All data will be entered using a double-entry procedure performed by two different individuals.
Data analysis will be conducted in accordance with the intention-to-treat principle. Missing data will be handled using linear mixed effects models. Statisticians and chief investigators will work out an analysis plan and related forms before database lock. The analysis will include case distribution, comparison of basic values, compliance, effectiveness, factors that influence efficacy, and safety. Subgroup analysis will be performed to according to pathological classification and syndrome classification. statistical analysis will be conducted using SAS 9.2 (SAS Institute Inc., Cary, NC, USA). The Wilcoxon rank sum test,t test, or variance analysis will be performed for inter-group or intra-group comparison according to data distribution. The Wilcoxon rank sum test will be used to compare ranked data. The chi-square test will be applied to compare enumeration data. All tests will be one-sided. A p value <0.05 will be considered statistically significant.
Possiblea adverse events during Ma's bamboo-based medicinal moxibustion treatment include itching, scald, redness, blister and infection. Fainting, sticking of needle, hematoma, subcutaneous hematoma, and bleeding might occur during acupuncture treatment. Therapists and subjects are informed to actively report any adverse events during the study. Researchers will track the results of safety evaluation indexes (routine blood test, liver and kidney function, ECG) before and after treatment in a timely manner, and confirm the occurrence of adverse events. Any adverse events that occurs during the trial will be recorded in a CRF by researchers and patients will be treated as soon as possible.Patients may choose to withdraw from the trial due to any adverse events. The sponsor and the data management company INTELLIGENCE FUTURE will monitor the implementation of the trial protocol and filling of CRFs.